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【结 构 式】 
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【分子编号】51375 【品名】5-Nitro-2-furaldehyde; 5-Nitrofurfural 【CA登记号】698-63-5 |
【 分 子 式 】C5H3NO4 【 分 子 量 】141.08316 【元素组成】C 42.57% H 2.14% N 9.93% O 45.36% |
合成路线1
该中间体在本合成路线中的序号：(I)Reduction of 5-nitro-2-furaldehyde (I) with NaBH4 provided the corresponding alcohol (II). The phosphoramidic dichloride (IV) was prepared by treatment of bis(2-bromoethyl)amine (III) with phosphorus oxychloride in the presence of triethylamine at -40 C. Condensation of acid chloride (IV) with the lithium alkoxide of (II) at -78 C produced the intermediate (V), which was treated in situ with gaseous ammonia at -20 C, yielding the title phosphorodiamidate.
| 【1】 Joswig, C.; Marakovits, J.T.; Liu, J.; Mulcahy, R.T.; Borch, R.F.; Schmidt, J.P.; Gipp, J.J.; Synthesis and evaluation of nitroheterocyclic phosphoramidates as hypoxia-selective alkylating agents. J Med Chem 2000, 43, 11, 2258. |
合成路线2
该中间体在本合成路线中的序号：(II)The title compound is prepared by reductive alkylation of the known piperazinyl oxazolidinone derivative (I) with 5-nitro-2-furfural (II) in the presence of NaBH(OAc)3, followed by conversion to the corresponding hydrochloride salt.
| 【1】 Arora, S.K.; Mehta, A.; Rattan, A.; Das, B.; Ray, A.; Rudra, S. (Ranbaxy Laboratories Ltd.); Oxazolidinone derivs. as antimicrobials. EP 1303511; US 2002103186; WO 0206278; WO 0307870; WO 0308389 . |
合成路线3
该中间体在本合成路线中的序号：The antibacterial activity of RBx-7644 is due to the 5(S)-acetamidomethyl configuration at the oxazolidinone ring, and thus, asymmetric synthesis of only the 5(S)-enantiomer was desirable: 3,4-Difluoronitrobenzene (I) is condensed with piperazine in acetonitrile to give 4-(2-fluoro-4-nitrophenyl)-piperazine (II) as a light yellow compound. Compound (II) is dissolved in dichloromethane and triethylamine, followed by the addition of Boc-anhydride, to provide compound (III). 4-(tert-Butoxycarbonyl)-1-(2-fluoro-4-nitrophenyl)piperazine (III), upon hydrogenation with H2 over Pd/C in methanol at 50 psi, yields 4-(tert-butoxycarbonyl)-1-(2-fluoro-4-aminophenyl)piperazine (IV) as a dark solid. Compound (IV) reacts with benzylchloroformate in dry THF in the presence of solid sodium bicarbonate to afford the desired compound (V). 4-(tert-Butoxycarbonyl)-1-[2-fluoro-4-(benzyloxycarbonylamino)phenyl]piperazine (V), upon treatment with n-BuLi and (R)-glycidyl butyrate at -78 °C, gives the desired (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone (VI). The hydroxymethyl compound (VI) is treated with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(methylsulfonyloxymethyl)-2-oxazolidinone (VII). The sulfonyl derivative (VII) is treated with sodium azide in dimethylformamide to provide the azide (VIII) as a white solid. (R)-(-)-3-[3-Fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl]-5-(azidomethyl)-2-oxazolidinone (VIII), upon hydrogenation with H2 over Pd/C at 45 psi, gives (S)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)-piperazin-1-yl]phenyl]-5-(aminomethyl)-2-oxazolidinone (IX). The aminomethyl compound (IX), upon treatment with acetic anhydride in dichloromethane in the presence of triethylamine, affords the acetamide derivative (X). The acetamidomethyl-oxazolidinone derivative (X), upon treatment with trifluoroacetic acid, gives (S)-(-)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(acetamidomethyl)-2-oxazolidinone, which, without isolation, is treated with 5-nitro-2-furaldehyde in the presence of sodium triacetoxy borohydride to provide compound (XI). Compound (XI), upon treatment with ethanolic HCl, affords RBx-7644 as a light yellow crystalline solid.
| 【1】 Rattan, A.; RBx-7644. Drugs Fut 2003, 28, 11, 1070. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 | |
| 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 | |
| 51375 | 5-Nitro-2-furaldehyde; 5-Nitrofurfural | 698-63-5 | C5H3NO4 | 详情 | 详情 | |
| (I) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 18382 | 1-(2-fluoro-4-nitrophenyl)piperazine | C10H12FN3O2 | 详情 | 详情 | |
| (III) | 63060 | tert-butyl 4-(2-fluoro-4-nitrophenyl)-1-piperazinecarboxylate | C15H20FN3O4 | 详情 | 详情 | |
| (IV) | 63061 | tert-butyl 4-(4-amino-2-fluorophenyl)-1-piperazinecarboxylate | C15H22FN3O2 | 详情 | 详情 | |
| (V) | 63062 | tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)-1-piperazinecarboxylate | C23H28FN3O4 | 详情 | 详情 | |
| (VI) | 63063 | tert-butyl 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-piperazinecarboxylate | C19H26FN3O5 | 详情 | 详情 | |
| (VII) | 63064 | tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-1,3-oxazolidin-3-yl)phenyl]-1-piperazinecarboxylate | C20H28FN3O7S | 详情 | 详情 | |
| (X) | 63067 | tert-butyl 4-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-1-piperazinecarboxylate | C21H29FN4O5 | 详情 | 详情 | |
| (XI) | 63068 | N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide | C21H24FN5O6 | 详情 | 详情 |